Modification of hepatic drug-metabolizing enzymes in rats treated with alkyl sulfides.
Natural compounds which elevate detoxification enzymes and/or reduce activating enzymes could be considered as good candidates to protect against cancer. In this work, we studied the modulation of hepatic drug-metabolizing enzymes in rats treated with dimethyl sulfide (DMS), dimethyl disulfide (DMDS), methylpropyl disulfide (MPDS), dipropyl sulfide (DPS), dipropyl disulfide (DPDS) and diallyl disulfide (DADS) issued from Allium species. Compounds containing methyl groups had little or no effect. Compounds with two propyl groups or two allyl groups provoked a pleiotropic response on drug-metabolizing enzymes. DPS, DPDS and DADS induced ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase and mostly pentoxyresorufin O-depentylase and decreased nitrosodimethylamine N-demethylase and erythromycin N-demethylase. These modifications of enzyme activities were accompanied by an increase of CYP 2B1,2 and a decrease of CYP 2E1, evidenced by immunoblotting. The same treatments stimulated some phase II enzyme activities such as glutathione transferase and UDP-glucuronyl transferases. This pattern of induction and/or inhibition of drug metabolizing enzymes was qualitatively similar to that elicited by the enzyme inducer, phenobarbital. The magnitude of the effects produced by DPDS was smaller than those produced by DADS and DPS. Our results suggest a possible protective effect of alkyl sulfides as well as diallyl disulfide, on the first step of carcinogenesis via the modulation of enzymes involved in carcinogen metabolism.
Siess
M H
MH
Unité de Toxicologie Nutritionnelle, INRA, Dijon, France. siess@dijon.inra.fr
Le Bon
A M
AM
Canivenc-Lavier
M C
MC
Suschetet
M
M
D000498:Allyl Compounds; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004220:Disulfides / Q000302:isolation & purification / Q000494:pharmacology; D005737:Garlic / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009822:Oils, Volatile / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010946:Plants, Medicinal; D011407:Propane / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000302:isolation & purification / Q000494:pharmacology*
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; D009822:Oils, Volatile; D013440:Sulfides; C021181:dimethyl disulfide; C028009:diallyl disulfide; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; C041288:n-propyl disulfide; C087894:dipropyl sulfide; C004784:dimethyl sulfide; D011407:Propane; D010634:Phenobarbital